MN-166 (ibudilast) is an investigational therapy being developed by MediciNova to treat amyotrophic lateral sclerosis (ALS), progressive multiple sclerosis and drug dependence. MediciNova, based in La Jolla, California, has marketed the drug in Japan and South Korea since 1989 to treat post-stroke complications and bronchial asthma.
How MN-166 works
MN-166 is a small molecule that inhibits the action of enzymes called phosphodiesterase (PDE) -4 and -10 and that of macrophage migration inhibitory factor (MIF), which all play important roles in inflammation. MN-166 also blocks the activity of cell signaling molecules that play a role in inflammation and promote the survival, development and function of nerve cells. Finally, it attenuates activated glial cells, which play a major role in certain neurological conditions.
The anti-inflammatory and neuroprotective effects of MN-166 have been shown in preclinical and clinical studies.
MN-166 in clinical trials
A Phase 2 study (NCT02238626) is evaluating the safety, tolerability, and clinical responsiveness of 60 mg/day of MN-166 administered as an adjunct or add-on therapy to 100 mg/day of Rilutek (riluzole). The single center, randomized, double-blind, placebo-controlled study of 60 participants is no longer recruiting.
The study consists of two treatment arms, MN-166 and placebo. Participants are first being screened for up to three months, followed by a six-month double-blind phase in which neither patients nor clinicians know who is getting MN-166 and who is getting placebo. Those on placebo are then treated with open-label MN-166 for six months. The follow-up phase begins two weeks after the last dose.
During the treatment phase, participants return to the clinic at months 3 and 6 and are telephoned at months 1, 2, 4, and 5 to collect information about side effects and any other drugs they may be taking.
Researchers assess the safety of MN-166 by monitoring and recording all serious adverse events and discontinuations as a result of the treatment. Additional assessments include the monitoring of blood and urine values, vital signs, electrocardiograms (ECG), medical history, and physical and neurological examinations.
An exploratory interim analysis of 47 patients found significant decreases in muscle strength two weeks after stopping MN-166 treatment for hip, leg and neck flexion. Lower-motor-neuron ALS burden significantly deteriorated in limb-onset patients, but significant changes were not seen in bulbar-onset patients. (In bulbar-onset ALS, patients first experience symptoms in the head and neck, including trouble speaking or swallowing.) Medicinova presented the results in April 2017 at the American Academy of Neurology Annual Meeting in Boston.
New results from this trial were presented in December 2017, at the 28th International Symposium on ALS/MND (Amyotrophic Lateral Sclerosis/Motor Neurone Disease), also held in Boston.
The new data is from 51 patients without non-invasive ventilation (NIV) and shows that treatment with MN-166 is safe and well-tolerated (achieving the study’s primary endpoint), and more effective at improving patients’ function than placebo.
Seven serious adverse events were reported, but none were related to treatment. All adverse events related to treatment were mild to moderate; the most common were nausea, anorexia and loss of appetite.
More patients taking MN-166 responded to treatment as measured by the ALS functional rating scale-revised (ALSFRS-R) that looks at the functional activity of ALS patients, than those on placebo in the first six months (29.4% versus 17.6%). Additionally, 35.3% of patients who switched from placebo to MN-166 in the six-month extension period, responded when given MN-166.
As the disease progresses, patients usually have lower scores on the ALSFRS-R score. A responder was defined as a patient who had improved, had no change or declined by one point on the scale score. A non-responder was defined as a patient who declined by two points or more on the score.
More patients taking MN-166 than patients taking placebo also responded to treatment as measured by the ALS assessment questionnaire (ALSAQ-5) during the first six months of the study (50% versus 23.5%). Similarly, 29.4% of patients who switched from placebo to MN-166 in the six-month extension period responded when taking MN-166.
ALSAQ-5 measures the physical mobility, activities of daily living and independence, eating and drinking, communication, and emotional functioning of ALS patients. A responder was defined as a patient whose score improved or did not change, and a non-responder as a patient whose score declined.
In total, 43.1% of patients treated with MN-166 for six months were responders, a significantly higher number than the 23.5% of patients given placebo. Investigators considered that these results were encouraging and call for more studies of MN-166 in ALS.
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